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Radiotherapy and Oncology : Journal of... Sep 2023Standard treatment of squamous cell carcinoma of the anus (SCCA)is 5-fluorouracil (5FU) and mitomycin C (MMC) based chemoradiotherapy (CRT). This phase II study...
BACKGROUND AND PURPOSE
Standard treatment of squamous cell carcinoma of the anus (SCCA)is 5-fluorouracil (5FU) and mitomycin C (MMC) based chemoradiotherapy (CRT). This phase II study (EudraCT: 2011-005436-26) assessed the tolerance and complete response (CR) rate at 8 weeks of panitumumab (Pmab) combined with MMC-5FU-based CRT.
METHODS
Patients with locally advanced tumors without metastases (T2 > 3 cm, T3-T4, or N + whatever T stage) were treated with IMRT up to 65 Gy and concomitant CT according to the doses defined by a previous phase I study (MMC: 10 mg/m; 5FU: 400 mg/m; Pmab: 3 mg/kg). The expected CR rate was 80%.
RESULTS
Forty-five patients (male: 9, female: 36; median age: 60.1 [41.5-81]) were enrolled in 15 French centers. The most common related grade 3-4 toxicities observed were digestive (51.1%), hematologic (lymphopenia: 73.4%; neutropenia: 11.1%), radiation dermatitis (13.3%), and asthenia (11.1%) with RT interruption in 14 patients. One patient died because of mesenteric ischemia during the CRT, possibly related to treatment. In ITT analysis, the CR rate at 8 weeks after CRT was 66.7% [90%CI: 53.4-78.2]. Median follow-up was 43.6 months [IC 95%: 38.61-47.01]. Overall survival, recurrence-free and colostomy-free survival at 3 years were 80% [95%CI: 65.1-89], 62.2% [IC95%: 46.5-74.6] and 68.8 % [IC95%: 53.1-80.2] respectively.
CONCLUSION
Panitumumab in combination with CRT for locally advanced SCCA failed to meet the expected CR rate and exhibited a poor tolerance. Furthermore, late RFS, CFS, and OS did not suggest any outcome improvement to justify further clinical trials.
CLINICALTRIALS
gov identifier: NCT01581840.
Topics: Humans; Male; Female; Middle Aged; Anal Canal; Panitumumab; Anus Neoplasms; Chemoradiotherapy; Fluorouracil; Mitomycin; Antineoplastic Combined Chemotherapy Protocols; Cisplatin
PubMed: 37315583
DOI: 10.1016/j.radonc.2023.109742 -
Bioengineering (Basel, Switzerland) Apr 2024Excessive fibrosis and resultant poor control of intraocular pressure (IOP) reduce the efficacy of glaucoma surgeries. Historically, corticosteroids and anti-fibrotic... (Review)
Review
Excessive fibrosis and resultant poor control of intraocular pressure (IOP) reduce the efficacy of glaucoma surgeries. Historically, corticosteroids and anti-fibrotic agents, such as mitomycin C (MMC) and 5-fluorouracil (5-FU), have been used to mitigate post-surgical fibrosis, but these have unpredictable outcomes. Therefore, there is a need to develop novel treatments which provide increased effectiveness and specificity. This review aims to provide insight into the pathophysiology behind wound healing in glaucoma surgery, as well as the current and promising future wound healing agents that are less toxic and may provide better IOP control.
PubMed: 38790314
DOI: 10.3390/bioengineering11050446 -
International Journal of Molecular... Aug 2023Osteoarthritis (OA) is a chronic joint disease characterized by articular cartilage calcification, loss of articular cartilage, bone changes, pain, and disability....
Osteoarthritis (OA) is a chronic joint disease characterized by articular cartilage calcification, loss of articular cartilage, bone changes, pain, and disability. Cartilage calcification is one hallmark of OA and is predominantly caused by basic calcium crystals formed due to an imbalance of the pyrophosphate pathway. Sortilin is a transmembrane protein that contributes to vascular calcification in atherosclerosis by externalizing alkaline phosphatase (ALP)-containing vesicles. Calcification in atherosclerosis and osteoarthritis has been associated with cellular senescence. The aim of this study was to investigate the potential role of sortilin and senescence in osteoarthritis-dependent cartilage calcification. Osteoarthritic cartilage from human knee joints was collected after joint replacement, and samples were analyzed by immunohistochemistry and quantitative RT-PCR analysis. Human chondrocytes were treated with osteogenic medium for up to 21 days to induce calcification. Western blots for sortilin and ALP, as well as an ALP activity assay, were performed. Human chondrocytes were treated with mitomycin C to induce senescence, and sortilin expression was quantified at the protein and gene levels. Sections of knee joints from a murine model of osteoarthritis were stained for sortilin and p16 and analyzed by immunohistochemistry. Treatment of wild-type chondrocytes using an osteogenic medium similar to human chondrocytes was performed. Osteoarthritic cartilage from mouse and human knee joints showed an increased number of sortilin and p16-positive chondrocytes compared to healthy cartilage. This observation was corroborated by increased gene expression of sortilin and p16 in mild and moderate osteoarthritic cartilage samples. To investigate the mechanism of sortilin regulation, human chondrocytes were treated with osteogenic medium to induce calcification. Sortilin protein levels and expression were increased after 7 days of stimulation, whereas ALP levels and activity were upregulated after 21 days of stimulation. Similar observations were made in a murine osteoarthritis model. Mechanistically, senescent chondrocytes induced by mitomycin C showed an upregulation of sortilin and ALP gene expression compared to non-senescent chondrocytes. Our data indicate that sortilin and ALP are upregulated during cartilage calcification, which is associated with chondrocyte senescence and thus might contribute to the pathogenesis of osteoarthritis. Cellular senescence seems to induce sortilin expression.
PubMed: 37569721
DOI: 10.3390/ijms241512343 -
Translational Andrology and Urology Sep 2023Upper urinary tract urothelial carcinomas (UTUCs) are often identified and first treated endoscopically. After proper risk stratification, adjuvant treatment may be... (Review)
Review
Upper urinary tract urothelial carcinomas (UTUCs) are often identified and first treated endoscopically. After proper risk stratification, adjuvant treatment may be recommended. Consequently, as adjuvant therapy becomes more common place in the oncological armamentarium, we seek to better characterize its existing and future therapeutic landscape. In this article, we present an overview of the most up-to-date information about intracavitary instillations as an adjuvant therapy in the context of UTUC. We reviewed the current literature on the epidemiology, disease characteristics, treatment, and outcomes of UTUC with a particularly focus on intraluminal adjuvant therapy for UTUC. This review provides a comprehensive overview of the most recent available data regarding adjuvant therapies used for UTUC. Intraluminal therapy plays an increasingly important role in the management of UTUC. Mitomycin C is the most common adjuvant treatment for UTUC with bacillus Calmette-Guerin (BCG) being utilized to a lesser extent. UGN-101 is a novel topical gel-based therapy that has shown promising results and thus recently garnered Food and Drug Administration (FDA) approval for UTUC. Other treatments such as BCG-IFN, gemcitabine, docetaxel, and drug-eluting stents (DES) may play a future role in UTUC treatment given further research. It is important to caveat that current studies on topical adjuvant treatments demonstrate varying degrees of effectiveness. This is largely due to limited research on UTUC, consisting of small sample sizes, and mostly retrospective experiences. Accordingly, further clinical trials are needed to evaluate the true benefit of these treatments.
PubMed: 37814698
DOI: 10.21037/tau-23-35 -
Genetics in Medicine : Official Journal... Jul 2023Rothmund-Thomson syndrome (RTS) is characterized by poikiloderma, sparse hair, small stature, skeletal defects, cancer, and cataracts, resembling features of premature...
PURPOSE
Rothmund-Thomson syndrome (RTS) is characterized by poikiloderma, sparse hair, small stature, skeletal defects, cancer, and cataracts, resembling features of premature aging. RECQL4 and ANAPC1 are the 2 known disease genes associated with RTS in >70% of cases. We describe RTS-like features in 5 individuals with biallelic variants in CRIPT (OMIM 615789).
METHODS
Two newly identified and 4 published individuals with CRIPT variants were systematically compared with those with RTS using clinical data, computational analysis of photographs, histologic analysis of skin, and cellular studies on fibroblasts.
RESULTS
All CRIPT individuals fulfilled the diagnostic criteria for RTS and additionally had neurodevelopmental delay and seizures. Using computational gestalt analysis, CRIPT individuals showed greatest facial similarity with individuals with RTS. Skin biopsies revealed a high expression of senescence markers (p53/p16/p21) and the senescence-associated ß-galactosidase activity was elevated in CRIPT-deficient fibroblasts. RECQL4- and CRIPT-deficient fibroblasts showed an unremarkable mitotic progression and unremarkable number of mitotic errors and no or only mild sensitivity to genotoxic stress by ionizing radiation, mitomycin C, hydroxyurea, etoposide, and potassium bromate.
CONCLUSION
CRIPT causes an RTS-like syndrome associated with neurodevelopmental delay and epilepsy. At the cellular level, RECQL4- and CRIPT-deficient cells display increased senescence, suggesting shared molecular mechanisms leading to the clinical phenotypes.
Topics: Humans; Rothmund-Thomson Syndrome; Cellular Senescence; DNA Damage; Hydroxyurea; Fibroblasts; Mutation; Adaptor Proteins, Signal Transducing
PubMed: 37013901
DOI: 10.1016/j.gim.2023.100836 -
Cancers Sep 2023To review the latest evidence on the modern techniques and outcomes of kidney-sparing surgeries (KSS) in patients with upper tract urothelial carcinoma (UTUC). (Review)
Review
PURPOSE
To review the latest evidence on the modern techniques and outcomes of kidney-sparing surgeries (KSS) in patients with upper tract urothelial carcinoma (UTUC).
METHODS
A comprehensive literature search on the study topic was conducted before 30 April 2023 using electronic databases including PubMed, MEDLINE, and EMBASE. A narrative overview of the literature was then provided based on the extracted data and a qualitative synthesis of the findings.
RESULTS
KSS is recommended for low- as well as select high-risk UTUCs who are not eligible for radical treatments. Endoscopic ablation is a KSS option that is associated with similar oncological outcomes compared with radical treatments while preserving renal function in well-selected patients. The other option in this setting is distal ureterectomy, which has the advantage of providing a definitive pathological stage and grade. Data from retrospective studies support the superiority of this approach over radical treatment with similar oncological outcomes, albeit in select cases. Novel chemoablation agents have also been studied in the past few years, of which mitomycin gel has received FDA approval for use in low-risk UTUCs.
CONCLUSION
KSSs are acceptable approaches for patients with low- and select high-risk UTUCs, which preserve renal function without compromising the oncological outcomes.
PubMed: 37760465
DOI: 10.3390/cancers15184495 -
Current Oncology (Toronto, Ont.) Sep 2023Since EXTRA, a non-randomized phase II trial with 31 patients, explored the use of capecitabine, mitomycin and radiation therapy (RT) in the treatment of localized...
Since EXTRA, a non-randomized phase II trial with 31 patients, explored the use of capecitabine, mitomycin and radiation therapy (RT) in the treatment of localized squamous cell carcinoma of the anal canal (SCCAC), this treatment has been considered as an acceptable alternative to infusional 5-FU. However, the differences in efficacy between capecitabine and 5-FU in chemoradiation therapy (CRT) with simultaneous integrated boost (SIB) radiation therapy (SIB-IMRT) for local SCCAC are not well documented. Patients included in this prospective monocentric cohort study were treated with SIB-RapidArc (a unique RT method treatment for all patients: identical technique, volume and constraints for at-risk organs), mitomycin C and 5-FU each day of RT for 7 weeks (group 1) or capecitabine each day of RT (group 2). Patients treated between July 2009 and August 2017 (group 1) and between November 2012 and April 2018 (group 2) for local SCCAC T2-4 classified as N, M0 or T, N1-3, M0 were included. Primary endpoints were progression-free survival (PFS) and acute toxicities. Results: One hundred forty-seven patients were included, 91 in group 1 and 56 in group 2. The two groups were statistically comparable in terms of sex, Eastern Cooperative Oncology Group Performance Status (ECOG PS) and TNM. With a median duration of follow-up of 53.5 months, the PFS rate at 3 years was 80% for group 1 and 75% for group 2 ( = 0.32). The 3-year colostomy-free survival rate was 92% for group 1 and 85% for group 2 ( = 0.11). The rate of patients with at least one grade 3 or higher acute toxicity was 35.5% in group 1 and 21.4% in group 2 ( = 0.10), with a trend of fewer acute toxicities with capecitabine. Conclusion: Capecitabine/mitomycin in combination with SIB RapidArc radiation therapy for anal cancer seems as effective as 5-FU-based chemotherapy and is well tolerated with minimal toxicity.
Topics: Humans; Mitomycin; Capecitabine; Fluorouracil; Radiotherapy, Intensity-Modulated; Cohort Studies; Prospective Studies; Anus Neoplasms
PubMed: 37754536
DOI: 10.3390/curroncol30090621 -
Cureus Sep 2023Non-muscle invasive bladder cancer (NMIBC) is a frequently diagnosed neoplasm, which is typically managed with transurethral resection of bladder tumor (TURBT)...
INTRODUCTION
Non-muscle invasive bladder cancer (NMIBC) is a frequently diagnosed neoplasm, which is typically managed with transurethral resection of bladder tumor (TURBT) eventually followed by intravesical therapies. Bacillus Calmette-Guérin (BCG) is used as first-line adjuvant treatment in high- (HR) and intermediate-risk (IR) NMIBC, although, in the latter, mitomycin C (MMC) may also be used. Multiple limitations to the use of BCG encouraged the search for therapeutic alternatives. In this context, hyperthermic intravesical chemotherapy with MMC (HIVEC-MMC) emerged as a promising therapy in the adjuvant setting for NMIBC. The aim of our study was to evaluate the tolerability, compliance, and survival outcomes of HIVEC-MMC in patients with IR- and HR-NMIBC.
MATERIAL AND METHODS
This was a single-center retrospective analysis of IR- and HR- NMIBC patients who received HIVEC-MMC after TURBT between August 2018 and August 2022. Levels of risk stratification were defined using the European Association of Urology (EAU) criteria. The protocol consisted of four weekly HIVEC-MMC instillations (induction) followed by six monthly instillations (maintenance). The primary outcomes were to evaluate the tolerability and compliance with the HIVEC-MMC protocol and secondary outcomes were disease-free survival (DFS) and overall survival (OS). For the purpose of statistical analysis, methods of descriptive statistics, survival analysis (Kaplan-Meier estimation), and multivariate analysis (Cox regression, and binary logistic regression) were used.
RESULTS
Fifty-seven patients were enrolled with a median age of 67.9 (34.4-83.5) years old. In this cohort, 40 patients (70.2%) had primary tumors. At the time of referral for HIVEC-MMC, the majority of the patients had IR-NMIBC (n= 33, 57.9%). A total of 41 patients (71.9%) completed the HIVEC-MMC protocol. Disease recurrence and adverse events (AEs) were the most common reasons to stop the protocol. After a median follow-up of 31 months (95% CI, 5.0-54.0), 32 patients (61.4%) were disease-free, 22 (38.6%) experienced recurrent disease and six patients (10.5%) died, although only one death was directly attributable to bladder cancer. The median DFS was 42 months (95% CI, 28.0-56.0). Completion of the HIVEC-MMC maintenance phase protocol stood as a predictive factor for DFS (44 months, 95% CI 29.1-58.9 vs. 14 months, 95% CI 0.0-29.6, p < 0.001; HR 4.48, 95% CI 1.65-12.15). The median OS was not reached; the 24- and 48-month OS were 92.6% and 82.7%, respectively. EAU risk group, ECOG-PS, and completion of HIVEC protocol were found to be significant predictive factors of OS but lost their significance on multivariate analysis. However, if we exclude those who experienced recurrence during the maintenance phase protocol, treatment completion had a significant positive impact on OS (HR: 42.8, 95% CI 1.75-1045.072, p= 0.021).
CONCLUSIONS
Our study suggests that HIVEC is a secure and well-tolerated treatment with promising efficacy data, making this therapeutic approach a feasible option in IR- and HR-NMIBC patients, mainly in those who cannot tolerate or have contraindications to BCG therapy, but also as an alternative during BCG shortages.
PubMed: 37745737
DOI: 10.7759/cureus.45672 -
International Journal of Ophthalmology 2023To evaluate the safety and efficacy of posterior scleral application (a modified technique) of an antimetabolite mitomycin C-soaked sponge in trabeculectomy for patients...
AIM
To evaluate the safety and efficacy of posterior scleral application (a modified technique) of an antimetabolite mitomycin C-soaked sponge in trabeculectomy for patients with glaucoma.
METHODS
This retrospective study included 101 patients (115 eyes) with glaucoma (aged 12-83y) who underwent trabeculectomy using a modified mitomycin C-soaked sponge placement method. A piece of 3.5×10 mm sponge was placed vertically and posteriorly with the long side perpendicular to the limbus. The mitomycin C concentration and exposure time were 0.2-0.5 mg/mL and 1-5min, respectively. Intraocular pressure, best-corrected visual acuity, and hypotensive medications were recorded at baseline and at the final visit. Complications, interventions required, and bleb morphology were recorded postoperatively. The primary outcome was trabeculectomy safety, including complications and bleb morphology; the secondary outcome was the trabeculectomy success rate.
RESULTS
At the final follow-up [median 28mo, range 7-67mo and interquartile range (IQR) 13mo], the qualified (cumulative) success rate was 93.0% and the complete success rate was 60.0%. No bleb-related complications were observed. The mean height, extent, and vascularity grades were 0.6±0.9, 1.1±0.4, and 2.4±0.9, respectively. All Seidel tests were negative. The mean posteriority grade was 0.8±0.4.
CONCLUSION
Trabeculectomy with the long side of a mitomycin C-soaked sponge placed perpendicular to the corneal limbus is safe and effective.
PubMed: 37465513
DOI: 10.18240/ijo.2023.07.11 -
International Journal of Molecular... Jul 2023Fanconi anemia (FA) develops due to a mutation in one of the FANC genes that are involved in the repair of interstrand crosslinks (ICLs). FANCG, a member of the FA core...
Fanconi anemia (FA) develops due to a mutation in one of the FANC genes that are involved in the repair of interstrand crosslinks (ICLs). FANCG, a member of the FA core complex, is essential for ICL repair. Previous FANCG-deficient mouse models were generated with drug-based selection cassettes in mixed mice backgrounds, leading to a disparity in the interpretation of genotype-related phenotype. We created a -KO (KO) mouse model using CRISPR/Cas9 to exclude these confounders. The entire locus was targeted and maintained on the immunological well-characterized C57BL/6J background. The intercrossing of heterozygous mice resulted in sub-Mendelian numbers of homozygous mice, suggesting the loss of FANCG can be embryonically lethal. KO mice displayed infertility and hypogonadism, but no other developmental problems. Bone marrow analysis revealed a defect in various hematopoietic stem and progenitor subsets with a bias towards myelopoiesis. Cell lines derived from -KO mice were hypersensitive to the crosslinking agents cisplatin and Mitomycin C, and -KO mouse embryonic fibroblasts (MEFs) displayed increased γ-H2AX upon cisplatin treatment. The reconstitution of these MEFs with cDNA corrected for the ICL hypersensitivity. This project provides a new, genetically, and immunologically well-defined -KO mouse model for further in vivo and in vitro studies on FANCG and ICL repair.
Topics: Humans; Animals; Mice; Cisplatin; Fanconi Anemia; Mice, Inbred C57BL; CRISPR-Cas Systems; DNA-Binding Proteins; Fibroblasts; Mitomycin; Phenotype; Fanconi Anemia Complementation Group G Protein
PubMed: 37446306
DOI: 10.3390/ijms241311129